Project Summary: Project 1, Perturbations and Behavior Working memory, the ability to temporarily hold multiple pieces of information in mind for manipulation, is central to virtually all cognitive abilities. This multi-component research project aims to comprehensively dissect the neural circuit mechanisms of this ability across multiple brain areas. The individual parts of the project cohere conceptually, in part, because they all involve rodents trained to perform a type of decision-making task that is based on the gradual accumulation of sensory evidence and thus relies on working memory. Neural correlates of working memory and decision-making are distributed across a very wide range of cortical and subcortical regions, but a complete listing of which of these regions actually cause these processes?and most importantly, what the nature of their contribution might be?remains out of reach. A significant obstacle has been that these processes can evolve rapidly (for example, going from loading an item into working memory, to holding it in memory, to retrieving it) and it is only recently that inactivation tools, such as inhibitory optogenetic molecules, could be turned on and off fast enough to distinguish between different phases. This project will use optogenetic inactivation in combination with this set of closely related working memory and decision-making tasks for the head-fixed rodent. The tasks are amenable to highly quantitative behavioral analysis. These features will allow a systematic and comprehensive quantitative probe of the causal contribution to working memory and decision-making of a very large set of regions across the dorsal cortex, deeper cortices, and targeted subcortical regions, including the cerebellum, the ventral tegmental area, the hippocampus, and the striatum. Other experiments will study the causal contributions of different genetically defined cell types, in targeted brain regions. Taken together, these experiments are expected to provide detailed information about how the interaction of particular neurons in the brain produces working memory and decisions, increasing knowledge about the brain basis of cognition.